Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.
Gastrointestinal-type cancers are malignant conditions which occur in the gastrointestinal tract including the stomach, oesophagus, liver, biliary system, pancreas, bowels and anus. Cancer of the stomach, generally referred to as gastric cancer (GC), is the second most common cause of cancer-related deaths worldwide (Parkin et al, CA Cancer J Clin 55:74-108, 2005). The high mortality and morbidity rate of GC highlights the need and imperative to develop effective treatments.
Although the molecular mechanisms underlying the pathogenesis of GC remain to be fully defined, a causal correlation has been established between GC and chronic inflammation triggered by the Gram-negative bacterium, Helicobacter pylori (Uemura et al, N Engl J Med 345:784-789, 2001) which colonizes the epithelium of the gastric mucosa. Several genetic factors have also been linked to GC, including accumulation of (epi-) genetic alterations in p53 (Wang et al, Anticancer Res. 21:513-520, 2001), tff1 (Park et al, Gastroenterology 119:691-698, 2000), E-cadherin (Guilford et al, Nat Med 392:402-405, 1998), Cox2 (Rocco et al, Annals of Oncology 17:103-108, 2006) as well as genes encoding components of the transforming growth factor (TGF)-β/Smad signaling cascade (Takaku et al, Cancer Res. 59:6113-6117, 1999; Xu et al, Oncogene 19:1868-1874, 2000; Massague et al, Cell 103:295-309, 2000; Boivin et al, Lab Invest. 74:513-518, 1996). Persistent activation of the latent signal transducer and activator of transcription (STAT) 3 has been proposed as a prognostic factor for poor survival of GC patients (Gong et al, Clin Cancer Res. 11:1386-1393, 2005), while excessive STAT3 activation promotes the growth and survival of gastric cells (Kanda et al, Oncogene 23:4921-4929, 2004; Kanai et al, Oncogene 22:548-554, 2003) and is associated with increased gastric angiogenesis (Gong et al, 2005 supra).
Interleukin (IL)-11 (IL-11) is a member of the IL-6 cytokine family which also comprises IL-27, IL-31, leukemia inhibitory factor (LIF), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF) amongst others, and plays a crucial role in hematopoiesis, the immune response and inflammation (Becker et al, Cell Cycle 4:217-220, 2005; Naugler et al, Science 317:121-124, 2007; Kishimoto et al, Blood 86:1243-1254, 1995). IL-6 family cytokines execute their actions via the common signal-transducing receptor β-subunit, gp130. In particular, binding of IL-6 or IL-11 to their specific receptor α-subunits, IL-6Rα and IL-11Rα, respectively, induces gp130 homodimerization, while other family members engage heterodimeric receptor complexes comprising gp130 and either the LIF-receptor (R), OSM-R or WSX-1 β-subunits (Heinrich et al, Biochem J. 374:1-20, 2003). Ligand-induced β-subunit dimerization subsequently activates receptor-associated Janus kinases (Jak), leading to phosphorylation of cytoplasmic Y residues (Heinrich et al, Biochem J 334(Pt 2):297-314, 1998). Phosphorylation of the four carboxy-terminal Y residues in gp130 is required and sufficient for the activation of STAT3 and to a lesser extent of STAT1 (Gerhartz et al, J. Biol. Chem. 271:12991-12998, 1996). Meanwhile, the membrane-proximal phosphorylated Y residue in gp130 (pY757 in mouse, pY759 in human) provides a binding site for the tyrosine phosphatase Shp2 (Nicholson et al, Proc Natl Acad Sci USA 97:6493-6498, 2000), which upon phosphorylation mediates activation of the Ras/Erk and PI3K/Akt pathways (Takahashi-Tezuka et al, Mol Cell Biol. 18:4109-4117, 1998).
STAT3 induces expression of genes associated with angiogenesis (e.g. VEGF), cell cycle progression (e.g. cylin D1) and cell survival (e.g. Bcl-XL, survival) [Jenkins et al, Nat Med 11:845-852, 2005]. Furthermore, persistent STAT3 activity appears to be associated with hematologic malignancies and tumors of epithelial origin (Gong et al, 2005 supra; Kanda et al, 2004 supra; Jenkins et al, 2005 supra; Levy and Lee, J Clin Invest 109:1143-1148, 2002).
De-regulated activation of the latent STAT3 is associated with a number of hematological and epithelial malignancies, including GC. Whilst exaggerated STAT3 and/or STAT1 signaling facilitates an anti-apoptotic, pro-angiogenic and pro-proliferative environment for neoplastic cells, the molecular mechanisms leading to STAT3 and/or STAT1 hyperactivation have been poorly understood.
There is a need to develop therapies for gastrointestinal-type cancers and in particular GC and colorectal cancer.